PROJECT SUMMARY/ABSTRACT Pediatric liver disease has significant morbidity and mortality. Biliary atresia (BA) accounts for more than half of pediatric liver transplants. Genetic causes of neonatal cholestasis include Alagille's syndrome (ALGS), alpha-1 antitrypsin deficiency (A1AT), Progressive Familial Intrahepatic Cholestasis (PFIC), bile acid synthetic defects, mitochondrial hepatopathies, and cystic fibrosis (CF). All of these diseases can progress to cirrhosis. The goals of the ChiLDReN network are to follow large numbers of these subjects longitudinally to allow accumulation of clinical data and biospecimens for studies that can help diagnose, use biomarkers to prognosticate for, and treat these diseases. Translational research founded on this remarkable database and biorepository can result in new insights regarding pathogenesis, disease modifiers, and ultimately therapy. We propose to continue participation in the ChiLDReN Research Network; our center will recruit patients with ChiLDReN diseases aggressively, retain them for longitudinal follow-up, and contribute to ongoing studies. We will continue to actively participate in the IMAGINE clinical trial studying the effect of an intestinal bile-acid transport inhibitor on pruritus. We will continue to participate in the longitudinal FORCE study of transient elastography to monitor hepatic fibrosis in children with biliary atresia, A1AT, and ALGS. The CF studies will continue to evaluate the role of ultrasound in predicting the development of cirrhosis in children with CF (PUSH), the role of transient elastography (ELASTIC), and magnetic resonance elastography (MRE) to non-invasively monitor fibrosis progression, and the progression of cirrhosis in this disease. We will participate in the development and implementation of the Primary Sclerosing Cholangitis (PSC) study, beginning with a database study and progressing to a clinical trial. The ultimate goal of the network is to learn more about natural history and pathogenesis in order to inform therapy and clinical management of cholestatic diseases in children. The Pilot and Feasibility clinical trial proposed by the IU center is a study of Minimal Hepatic Encephalopathy (MHE) in children with cirrhosis/portal hypertension due to biliary atresia. A panel of neurocognitive tests of executive function and a parent survey instrument will be used to evaluate children with biliary atresia-related cirrhosis. Children who are diagnosed with MHE will participate in a clinical trial of lactulose therapy, acting as their own control, with repeat neurocognitive testing after 3 months. ChiLDReN data will be used to begin to examine risk factors for the condition. This pilot will generate data about the frequency of this important sequela of chronic liver disease and guide future multicenter studies investigating its treatment.